11-119107976-G-T

Variant names:

• chr11-119107976-G-T
• rs746082840
• NM_001290474.2:c.235G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001290474.2(C2CD2L):​c.235G>T​(p.Ala79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 1,555,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: C2CD2L NM_001290474.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.697
• Publications: 0 publications found

Genes affected

C2CD2L (HGNC:29000): (C2CD2 like) Enables phosphatidylinositol binding activity and phosphatidylinositol transfer activity. Involved in positive regulation of insulin secretion involved in cellular response to glucose stimulus. Located in cortical endoplasmic reticulum and endoplasmic reticulum-plasma membrane contact site. Colocalizes with cytoplasmic side of apical plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

DPAGT1 (HGNC:2995): (dolichyl-phosphate N-acetylglucosaminephosphotransferase 1) The protein encoded by this gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. This enzyme belongs to the glycosyltransferase family 4. This protein is an integral membrane protein of the endoplasmic reticulum. The congenital disorder of glycosylation type Ij is caused by mutation in the gene encoding this enzyme. [provided by RefSeq, Jul 2008]

DPAGT1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• DPAGT1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040995866).
• BS2: High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290474.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD2L	NM_001290474.2	MANE Select	c.235G>T	p.Ala79Ser	missense	Exon 1 of 14	NP_001277403.1	O14523-1
	C2CD2L	NM_014807.5		c.235G>T	p.Ala79Ser	missense	Exon 1 of 14	NP_055622.3
	C2CD2L	NM_001382613.1		c.235G>T	p.Ala79Ser	missense	Exon 2 of 15	NP_001369542.1	O14523-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD2L	ENST00000648610.2	MANE Select	c.235G>T	p.Ala79Ser	missense	Exon 1 of 14	ENSP00000497391.1	O14523-1
	C2CD2L	ENST00000336702.7	TSL:1	c.235G>T	p.Ala79Ser	missense	Exon 1 of 14	ENSP00000338885.3	O14523-2
	C2CD2L	ENST00000861321.1		c.235G>T	p.Ala79Ser	missense	Exon 1 of 14	ENSP00000531380.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151916 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000599 AC: 1 AN: 166856 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1403260 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 698376

African (AFR) AF: 0.00 AC: 0 AN: 27854

American (AMR) AF: 0.0000903 AC: 3 AN: 33212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23304

East Asian (EAS) AF: 0.00 AC: 0 AN: 34470

South Asian (SAS) AF: 0.00 AC: 0 AN: 81004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5028

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090530

Other (OTH) AF: 0.0000174 AC: 1 AN: 57412

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 151916 Hom.: 0 Cov.: 30 AF XY: 0.0000809 AC XY: 6 AN XY: 74200

African (AFR) AF: 0.0000725 AC: 3 AN: 41368

American (AMR) AF: 0.000458 AC: 7 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000346 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.90
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.70
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.025
Sift	Benign	0.56	T
Sift4G	Benign	0.24	T
Polyphen		0.010	B
Vest4		0.040
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.043
MPC		0.44
ClinPred		0.045	T
GERP RS		2.7
PromoterAI		-0.018	Neutral
Varity_R		0.041
gMVP		0.34
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746082840; hg19: chr11-118978686;